RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:New PDC article mentionning TH1902 and TH1904That's the issue Jeff -- while sortilin exists in every cell (I think) and very little gets to the surface (one tenth) in a cell acting normally, it's the fact that in a tumor environment sortilin goes crazy and explodes in it's intensity and amount on the cell surface looking to "scavenge" that makes TH1902 work. The additional fact that it increases in relation to the severity and metastatic power of the cancer makes it a very attractive target for a cancer drug to latch on to. While sortilin has a function in other facets of the body it would be a different trick as it may not be the fact that cell death is the necessary therapy needed. You may just want to alter the issue in the cell and not kill it off. It's not like we use chemo bombs for things like Alzheimers, hypertension or any of the other diseases that have shown sortilin association. Whether you can find a drug for those disease that needs to get right in to the cells or not is probably an unanswered question since none of those diseases use targeted drugs like oncology does.
All this is way beyond me and I could very well be wrong, but my rudimentary understanding is even in the ADC world, if you find a target for cancer, you likely don't extend your drug platform to deal with other diseases with that same target. We have seen a few of the ADC firms where they go beyond just solid tumors or hematoma cancers and have things like eye diseases and other things. But the programs from the likes of Bicycle, SeaGen, Sutro, etc... are pretty varied in both targets and attached drugs.
I think the view folks like JFM would take (not putting words in his mouth) is that is the concept is valid, THTX will have their hands full for years trying differnent chemos for different cancers. So far, we've never heard of them developing any peptide beyond just this one that attaches to sortilin. They've claimed they have solid "peptide" developement skills (not really sure how to measure that or if that's actually correct), but it TH1902 and the peptide work, we don't really need to think about that additional avenue. If it comes, fine, but what they can do around sortilin if it's effective and useful is enormous in and of itself. It alone is a multi-billion opportunity if we get POC.
jfm1330 wrote: Sortilin is expressed at different levels in many organs and tissues, maybe every organs, I am not sure abot that, But anyway, it's pointless to talk about it as a target, unless it is significantly overexpressed, and the only cells where we know it is highly overexpressed is in some types of cancer, especially advanced ones.
jeffm34 wrote: The way the peptide works is that you can attach different drug molecules to it, not just docetaxal or other cytotoxic agents. It can deliver other therapeutic drugs as well. Why would you just administer the peptide on its own ? That's not how a PDC works
jfm1330 wrote: Again, to have a peptide ligand to sortilin does not mean you can alter the diffrent roles it can have in the metabolism. Again, naked peptide like TH19P01 have half lives that are very short. The do not remain intact in the bloodstream long enough to have any meaningful biological impact. It's like GRF (1-44), the natural peptide on which Egrifta (tesamorelin) is based. Tesamorelin is a stabilized version og GRF (1-44) by the addition of trans-3- hexenoix acid on the N-terminus of the peptide to slow down enzymatic degradation. Adding thwo docetaxel molecules to TH19P01, to form TH1902, is probably protecting TH19P01 to some extent from enzymatic degradation. Not stopping it, but slowing it down. So all that to say that Thera has nothing related to sortilin, except, hopefully, TH19P01 as a cytotoxic agent carrier.
jeffm34 wrote: https://www.liebertpub.com/doi/10.1089/dna.2017.3853
Sortilin facilitates hepatic cholesterol accumulation by inhibiting hepatic cholesterol catabolism, which promotes the development of nonalcoholic fatty liver disease (NAFLD). Sortilin plays an important role in lipid metabolism and represents a promising therapeutic target for lipid disorder diseases.
jfm1330 wrote: So far, TH19P01, the peptide involved in TH1902, which is a ligand of sortilin has shown no biological activity by itself, no anticancer effect without docetaxel. Also, bloodstream half lije of TH19P01 alone, not linked to two docetaxel molecules, is probably much shorter than the half life of TH1902. All that to say that having a peptide that is a ligand to sortilin and can act as drug carrier at the same time is a very specific application, a great one if it works, but this has nothing to do with other applications related to sortilin action and metabolism. In other word, TH19P01 is likely to only have value as a cytotoxic drug carrier in the context of cancers overexpressing sortilin. At this point it's impossible to see any other application. Also, let's remember that the cancer proof of concept in human still need to be established.
jeffm34 wrote: You can find articles on Sortilin and its involvement in lipid metabolism as well. There are potentially other applications for Theras peptide outside of oncology. The company said in their last call they are not interested in looking into other applications. Why are they not getting other companies or universities to do that for them ?